Pre- and Post-Treatment with Novel Antiepileptic Drug Oxcarbazepine Exerts Neuroprotective Effect in the Hippocampus in a Gerbil Model of Transient Global Cerebral Ischemia.

Ji Hyeon Ahn,Myoung Cheol Shin,Moo-Ho Won,Go Eun Yang,Young Eun Park,Bich Na Shin,Tae-Kyeong Lee,Jun Hwi Cho,Hyeyoung Kim,Joon Ha Park,Kyu Chang Lee,Jae-Chul Lee

doi:10.3390/brainsci9100279

Abstract

Oxcarbazepine, an antiepileptic drug, has been reported to modulate voltage-dependent sodium channels, and it is commonly used in epilepsy treatment. In this study, we investigated the neuroprotective effect of oxcarbazepine in the hippocampus after transient ischemia in gerbils. Gerbils randomly received oxcarbazepine 100 or 200 mg/kg before and after transient ischemia. We examined its neuroprotective effect in the cornu ammonis 1 subfield of the gerbil hippocampus at 5 days after transient ischemia by using cresyl violet staining, neuronal nuclei immunohistochemistry and Fluoro-Jade B histofluorescence staining for neuroprotection, and by using glial fibrillary protein and ionized calcium-binding adapter molecule 1 immunohistochemistry for reaction of astrocytes and microglia, respectively. Pre- and post-treatment with 200 mg/kg of oxcarbazepine, but not 100 mg/kg of oxcarbazepine, protected pyramidal neurons of the cornu ammonis 1 subfield from transient ischemic damage. In addition, pre- and post-treatment with oxcarbazepine (200 mg/kg) significantly ameliorated astrocytes and microglia activation in the ischemic cornu ammonis 1 subfield. In brief, our current results indicate that post-treatment as well as pre-treatment with 200 mg/kg of oxcarbazepine can protect neurons from ischemic insults via attenuation of the glia reaction.

Highlights

Transient global cerebral ischemia (TGCI) caused by a brief interruption of blood supply to the brain can develop the death or loss of neurons in vulnerable brain regions such as cornu ammonis 1 subfield (CA1) of the hippocampus [1]
Cresyl Violet (CV) staining showed all cells which were located in all layers: in particular, large CV-positive cells formed the stratum pyramidale (SP) in the hippocampus proper, which consisted of CA1-3 (Figure 1A,a)
We examined neuroprotective effect of pre- and post-treatment with 100 and 200 mg/kg OXC against damage by TGCI in the gerbil hippocampal CA1 region 5 days after 5-min TGCI by using NeuN immunohistochemistry and Fluoro-Jade B (FJB) histofluorescence staining, and we found that both pre- and post-treatment with

Summary

Introduction

Transient global cerebral ischemia (TGCI) caused by a brief interruption of blood supply to the brain can develop the death or loss of neurons in vulnerable brain regions such as cornu ammonis 1 subfield (CA1) of the hippocampus [1]. CA1 pyramidal neurons, are vulnerable to TGCI [2,3]. The CA1 neuronal loss is related to locomotor hyperactivity after TGCI in gerbils [6,7]. It has been known that the mechanisms of the death of the CA1 pyramidal neurons following TGCI include excitotoxicity by glutamate toxicity, oxidative stress via reactive oxygen species (ROS), neuroinflammation by glia cells, etc. AEDs displays beneficial effects to counteract neuronal damage or death from experimentally induced brain injuries, such as ischemic stroke, intracerebral hemorrhage and trauma [15]. Mechanisms of AEDs have been suggested four effects at the synaptic level: (i) regulation of voltage-dependent sodium channels, (ii) regulation of voltage-dependent calcium channels, (ii) improvement of GABA-mediated neuronal inhibition and (iv) decrease of glutamate mediated excitatory transmission [16]

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